Process for preparing solid dosage forms for unpalatable pharmaceuticals

ABSTRACT

A process for the preparation of a rapidly disintegrating dosage form a pharmaceutically active substance which has an unacceptable taste wherein there is formed a solution or a suspension in a solvent of a form of the pharmaceutically active substance which is less soluble in water and more palatable than the form with the unacceptable taste together with a water-soluble or water-dispersible carrier material. Discrete units of the suspension or solution are formed and the solvent is removed from the discrete units under conditions whereby a network of the carrier material carrying a dosage for the less soluble and more palatable form of the pharmaceutically active substance is formed.

RELATED APPLICATIONS

[0001] The present application is a continuation of U.S. patentapplication Ser. No. 09/551,361 filed Apr. 18, 2000, which is acontinuation-in-part of application Ser. No. 09/026,551 filed Feb. 20,1998 which is a continuation of application Ser. No. 08/330,936, filedOct. 28, 1994, now U.S. Pat. No. 5,738,875.

FIELD OF THE INVENTION

[0002] The present invention relates to a process for preparing solidpharmaceutical dosage forms and, in particular, to a process forpreparing a solid, oral, rapidly disintegrating dosage form of apharmaceutically active substance which has an unpleasant taste.

BACKGROUND OF THE INVENTION

[0003] Many pharmaceutically active substances are presented for oraladministration in the form of conventional oral dosage forms, includingtablets, pills or capsules. The tablet, pill or capsule generally has tobe swallowed with water so that the pharmaceutically active substancecan be absorbed via the gastrointestinal tract. For some patients,swallowing the tablet, pill or capsule is difficult or impossible andthis is particularly the case for pediatric patients and geriatricpatients. A similar difficulty is often encountered when trying toadminister tablets to non-human animals which may be uncooperative intaking tablets, pills or capsules.

[0004] Oral solid pharmaceutical dosage forms which rapidly disintegratein the mouth and methods for their preparation have been proposed inGB-A-1548022 and GB-A-2111423. The solid dosage forms, as disclosed inthese references, comprise an open matrix network carrying thepharmaceutically active substance, the open matrix comprising awater-soluble or water-dispersible carrier material which is inerttowards the pharmaceutically active substance. The solid dosage formsare prepared by the sublimation or removal of solvent from a solution orsuspension comprising the pharmaceutically active substance and thecarrier material. Sublimation or removal of solvent is preferablycarried out by freeze drying.

[0005] U.S. Pat. No. 5,382,437 to Ecanow discloses a readily dissolvedcarrier composition suitable for use in administration of drugs andfoodstuffs. The composition comprises a skeletal structure produced bycontacting a gel and a rigidifying material for the gel with liquifiedammonia at low temperature until the mass solidifies. As the mass isslowly warmed to ambient temperature under vacuum, the solid ammoniasublimes from the solid state to the gas state to provide a porous drugor foodstuff delivery system.

[0006] Other methods for the preparation of oral solid pharmaceuticaldosage forms which rapidly disintegrate in the mouth are disclosed inU.S. Pat. Nos. 4,855,326; 5,039,018; 5,120,549; 5,330,763;PCT/JP93/01631; PCT/US93/125661 and WO 98/57648, which are incorporatedherein by reference.

[0007] The solid dosage forms which are produced by these variousmethods rapidly disintegrate on being placed in th mouth of the patient,thereby delivering the desired dose of the pharmaceutically activesubstance.

[0008] Although the solid dosage forms as described above overcome theproblems of swallowing tablets, pills or capsules, the patient willtaste the pharmaceutically active substrate as the dosage formdisintegrates. For some pharmaceutically active substances, the taste,if slightly unpleasant, can be rendered acceptable by the use ofsweetening agents, flavoring agents and the like, which mask the taste.Yet, in some pharmaceutically active substances, the unpalatable tastewill still exist, despite the use of sweetening agents and flavoringagents. In those instances in which over-flavoring techniques alone willnot suffice, the insolubilization techniques of the present inventioncan result in palatable formulations.

SUMMARY OF THE INVENTION

[0009] Through the efforts of the present inventors, a new method forthe preparation of a solid, oral, rapidly disintegrating dosage form ofa pharmaceutically active substance which has an unacceptable taste hasbeen developed, which does not wholly depend upon trying to mask theunacceptable taste by the use of sweetening agents, flavoring agents andthe like. In general, the present invention uses the less soluble formto the drug to reduce or eliminate the use of sweetening agents, flavorand the like.

[0010] In a first aspect, the present invention provides a process forthe preparation of a solid, oral, rapidly disintegrating dosage form ofa pharmaceutically active substance which has an unacceptable taste. Theprocess comprises forming a solution or a suspension in a solvent of aform of the pharmaceutically active substance which is less soluble inwater than th form with the unacceptable taste, together with awater-soluble or water-dispersible carrier material, forming discreteunits of the solution or suspension. The solvent is then removed fromthe discrete units under conditions whereby a network of the carriermaterial carrying a unit dosage of the less soluble form of thepharmaceutically active substance is formed.

[0011] In another aspect, the invention provides a rapidlydisintegrating dosage form of a pharmaceutically active substance whenprepared by the process of the invention.

[0012] The present invention also includes within its scope, a solid,oral, rapidly disintegrating dosage form of a pharmaceutically activesubstance which has been rendered more palatable by the process asdescribed above.

[0013] The present invention is also directed to a solid, oral, rapidlydisintegrating dosage form comprising loperamide free base as thepharmaceutically active substance in a network of a carrier materialselected from the group consisting of water-soluble andwater-dispersible carrier materials.

[0014] Further, the invention discloses a solid, oral, rapidlydisintegrating dosage form comprising domperidone free base as thepharmaceutically active substance in a network of a carrier materialselected from the group consisting of water-soluble andwater-dispersible carrier materials.

DETAILED DESCRIPTION OF THE INVENTION

[0015] As used herein and in the claims, the term “rapidlydisintegrating” means that the solid dosage form will disintegrate inwater at 37° C. in 60 seconds or less, preferably 5 to 10 seconds orless, when tested by the following procedure which is analogous to theDisintegration Test for Tablets, B. P. 1973 and which is furtherdescribed in British Patent No. 1548022.

[0016] Disintegration Test—Apparatus

[0017] A glass or suitable tube 80 to 100 mm long, with an internaldiameter of about 38 mm and an external diameter of 30 to 31 mm andfitted at the lower end so as to form a basket, with a disc or rustproofwire gauze complying with the requirements for a No. 1.70 sieve (B. P.1983, page A136).

[0018] A glass cylinder with a flat base and an internal diameter ofabout 45 mm containing water and not less than 15 cm deep at atemperature between 36° C. and 38° C.

[0019] The basket is suspended centrally in the cylinder in such a waythat it can be raised and lowered repeatedly in a uniform manner so thatat the highest position, the gauze just breaks the surface of the waterand at the lowest position, the upper rim of the basket just remainsclear of the water.

[0020] Method

[0021] Place one shaped article (the rapidly disintegrating dosage form)in the basket and raise and lower it in such a manner that the completeup and down movement is repeated at a rate equivalent to thirty times aminute. The shaped articles are considered disintegrated when noparticle remains above the gauze which would not readily pass throughit.

[0022] On oral administration of the solid dosage form of the inventionto a patient, the pharmaceutical dosage form rapidly disintegrates inthe mouth. The rapidly disintegrating dosage form of the presentinvention enables poorly tasting pharmaceutically active substances tobe presented in a palatable form without changing the bioavailability ofthe pharmaceutically activ substance relative to an existing soliddosage form (i.e., pills and tablets) containing the more solublecompound. The pharmaceutically active substance is presented as a lesssoluble form rendering less of the drug to be tasted as the solid dosageform dissolves disintegrates in the saliva.

[0023] The pharmaceutically active substance with the unacceptable tastemay be presented in less soluble form prior to formation of the solutionor suspension. Alternatively, the pharmaceutically active form may beconverted into the less soluble form during the process of theinvention, for example during the preparation of the solution orsuspension.

[0024] The pharmaceutically active substance with the unacceptable tastemay be rendered less soluble by conversion of a salt to a free acid or afree base, or conversion of a free base to a salt, or changing the saltform to a less soluble salt form, or by using the common ion effect orsalting out, or changing the polymorphic form thereof, or by adjustingthe pH, or by any other suitable means. Each of these conversionapproaches may be carried out using methods well known to persons ofordinary skill in this art. In the publication “Pharmaceutics—TheScience of Dosage Form Design”; Ed. M. E. Aulton, Churchill Livingstoneprovides a general discussion of methods for conversion of drugs toforms of different solubility. The teachings of this reference areincorporated herein by reference.

[0025] The conversion of a salt to a free acid or free base may becarried out, for example, by the addition of an amount of acidic oralkaline agent to the salt and mixing of the resultant suspension untilthe solid salt has been neutralized to the free base form. The salt maybe dispersed in an appropriate amount of water along with the acidic oralkaline agent and any other excipients required to produce the dosageform. This mixture is then mixed continuously until the solid salt hasbeen converted to the respective free base or free acid. The amount ofacidic or alkaline agent needed is determined experimentally bypreparing formulations with varying amounts of the agent and performingtaste assessments on the finished product.

[0026] As a typical example of a salt to a free base, the hydrochloridesalt, e.g. Loperamide hydrochloride, may be converted to the free baseusing a bicarbonate buffer, such as for example sodium hydrogencarbonate buffer.

[0027] Conversion of a salt form to a less soluble salt form may beachieved by dispersing the salt in an aqueous medium and then adding therequired amount of an appropriate excipient salt. An appropriateexcipient salt is one which contains a counter-ion of opposite charge tothe dissolved drug and which has a stronger affinity for the drug thanthe counter-ion in the original drug salt. This mixture is agitateduntil the conversion is complete. The amount of acidic or alkaline agentneeded is determined experimentally by preparing formulations withvarying amounts of the agent and performing taste assessments on thefinished product

[0028] Pages 227-229 of Pharmaceutics, supra, illustrates methods forcalculation of the pH of a drug, the susceptibility of that drug to saltformation and the type of salt that can be formed. Examples ofpharmaceutically acceptable salts are hydrochloride, sulfate, besylate,maleate, tartrate, benzoate and citrate. By way of example of the effectof a particular salt form on solubility, for the drug Chlordiazepoxide,the following illustrates the differences in solubility of the differentsalts of the drug. Chlordiazepoxide sulfate or besylate are freelysoluble whereas Chlordiazepoxide base has a solubility of about 2.0 mgml⁻¹. Chlordiazepoxide maleate has a higher solubility of about 57.1 mgml⁻¹ whereas Chlordiazepoxide tartrate has a solubility of 17.9 mg ml⁻¹,Chlordiazepoxide benzoate has a solubility of 6.0 mg ml⁻¹ andChlordiazepoxide acetate has a solubility of 4.1 mg ml⁻¹.

[0029] The common ion effect or salting out may be used to reduce thesolubility. This is achieved by the addition of a soluble electrolyte ifthis contains a common ion to the drug to be dissolved. In effect, thedrug and the additional electrolyte are competing for the solvent, whichin turn reduces the solubility of the drug. An example of the common ioneffect (or salting out) is the addition of sodium bromid to anear-saturated solution of dextromethorphan hydrobromide to effectprecipitation of at least a portion of the drug. The effect may beexplained with reference to the solubility product, the constantequilibrium value of the product of the concentrations of the two ionicspecies arising from the drug. An added excess of one ion in the form ofa soluble salt will cause the solubility product to be exceeded, andthis will b corrected by removal of a proportion of both drug ions byprecipitation of solid drug.

[0030] The formation of a hydrate is typically achieved by stirring asuspension of the drug in water to effect conversion of the drug to thehydrate. Piroxicam monohydrat is produced progressively when asuspension of anhydrous piroxicam is stirred in water.

[0031] The polymorphic form may be changed in order to present thepharmaceutically active substance with the unacceptable taste in lesssoluble form prior to formation of the solution or suspension.Polymorphs are solid materials with at least two different moleculararrangements, each of which has a distinct crystal structure. Theparticular crystal state of a solid depends, at least in part, on thesolvent(s) used for recrystallization. Different polymorphic forms havedifferent stabilities, different oral bioavailabilities and differentsolubilities. A discussion of the phenomenon of polymorphism appears inWO 98/57648. The solubility of a crystalline form generally decreaseswith the increase in melting point of the crystalline form.Inter-conversion of polymorphs can occur spontaneously. The selection ofa less soluble polymorph can also be carried out by solventmanipulation, or by thermal techniques, notably sublimation andrecrystallization from the melt. These techniques are well known topersons of ordinary skill in this art.

[0032] The solubility of weak acids and weak bases may be adjusted by pHcontrol. Increasing the pH of a solution can decrease solubility of aweak base, whereas the solubility of a weak acid can be decreased by apH decrease. The relative levels of weak acid or weak base added to thedrug can be calculated with the knowledge of the Henderson-Hasselbalchequation, and by calculation of the pKa of the drug concerned in thesolvent in question.

[0033] For example, where Piroxicam is the drug of interest, the pH maybe adjusted in a manner which changes the ratio of the unionized toionized species, which in turn provides for an approximately tenfolddecrease in solubility, and a significant reduction in the bitter tasteof the drug. Piroxicam (Feldene) has a “U”-shaped pH solubility curvewith a minimum around pH 3.5. Typically, when Piroxicam is used in thesystem of the present invention, it exhibits a pH of about 6.5. This maybe adjusted to approximately 4.0 by addition of an add such as citricacid to produce the approximately tenfold decrease in solubility. Thisresults in a significantly reduced bitter taste by reducing the amountof dissolution in the mouth. A further advantag arising out of threduced solubility of Piroxicam is reduced formation of the hydratewhich has a bright yellow color.

[0034] Other ways of rendering the pharmaceutically active form lesssoluble are reducing the solubility of highly hydrophilic drugs in thepresence of an organic co-solvent. Bulking with less hydrophilicwater-soluble solutes may have a similar effect.

[0035] The discrete units of the suspension or solution may be in theform of liquid units, for example contained within the pockets of asuitable mold. The liquid units may alternatively be in the form ofgelled units where the carrier material readily forms a gel. Theseliquid units are then preferably frozen and the solvent removed viafreeze drying. The removal of solvent from the discrete units comprisingthe pharmaceutically active substance in its less soluble form and awater-soluble or water-dispersible carrier material may also be carriedout by other techniques well known to those skilled in the art. When thediscrete units are in liquid form, they will generally be frozen orgelled prior to drying.

[0036] The liquid solution or suspension which may be contained withinthe pockets of a suitable mold is frozen, for example by passing agaseous cooling medium, such as liquid nitrogen over the mold, or byinserting the mold into a nitrogen spray freezing chamber, or cooling bypassing the mold over a cold surface. Once the dosage forms have beenfrozen, the mold may be stored in a cold store, prior to drying. Frozendiscrete units may be dried by freeze drying according to techniqueswhich are well known in the art. The solvent is sublimed in a freezedrying process under a reduced pressure which transforms the solidsolvent directly into a vapor. The freeze drying process will generallybe carried out in a freeze drying chamber typically operating under avacuum of 0.1 to 1.0 mbar for a period of time of from 180 to 500minutes.

[0037] Alternatively, frozen discrete units may be dried by a process asdescribed in U.S. Pat. Nos. 5,120,549 and 5,330,763. In this method, thepharmaceutically active substance and carrier material dispersed in afirst solvent is solidified and th solidified matrix is subsequentlycontacted with a second solvent that is substantially miscible with thefirst solvent at a temperature lower than the solidification point ofthe first solvent, the matrix component being substantially insoluble inthe second solvent, the first solvent thereby being removed from thematrix.

[0038] Another alternative process for drying frozen discrete units isdescribed in WO94/14422. In this process the solvent is removed underconditions whereby the solvent is evaporated from the solid through theliquid phase to a gas, rather than subliming from a solid to a gas as inlyophilization. This is achieved by vacuum drying at a temperature belowthe equilibrium freezing point of the composition at which point thesolvent (such as water) changes phase.

[0039] When the discrete units are gelled units, any drying method canbe used which does not affect the properties of the preparations. Forexample, drying may be carried out at decreased pressure, or byforced-air drying. Drying at decreased pressure is preferably carriedout at a temperature of from 25° to 35° C. under a vacuum of −750 mm Hgor less, for 2 to 5 hours, while drying using forced-air drying ispreferably carried out at a temperature of from 30 to 15° C. for 1 to 6days.

[0040] The solvent used in forming the solution or suspension of thepharmaceutically active substance is preferably water but it may beadmixed with a co-solvent, such as alcohol, if it is desired to improvethe solubility of the active substance.

[0041] The carrier material which is used to form the network containingthe pharmaceutically active substance may be any water-soluble orwater-dispersible material that is pharmaceutically acceptable, inert tothe pharmaceutically active substance and which is capable of forming arapidly disintegrating network. The preferred carrier material for usein the present invention is gelatin, preferably pharmaceutical gradegelatin.

[0042] Other materials may also be used, for example hydrolyzeddextrose, dextran, dextrin, maltodextrin alginates,hydroxyethylcellulose, sodium carboxymethylcellulose, microcrystallinecellulose, corn-syrup solids, pectin, carrageenan, agar, chitosan,locust bean gum, xanthan gum, guar gum, acacia gum, tragacanth, konjacflour, rice flour, wheat gluten, sodium starch glycolate, soy fiberprotein, potato protein, papain, horse radish peroxidase, glycine ormannitol.

[0043] The suspension or solution prepared according to the process ofthe present invention is preferably formed into discrete units byintroduction into a mold which preferably comprises a plurality ofdepressions, each depression being of the desired shape and size for theoral dosage form product. The mold preferably comprises a plurality ofdepressions formed in a sheet of a filmic material which may be similarto the material employed conventionally in the blister packaging ofpharmaceuticals. A particularly preferred filmic material for use as amold in the present invention is described in WO94/12142. The desiredquantities of the suspension or solution may be filled into the moldusing an automatic filling means which delivers a predetermined doseinto each of the depressions in the mold.

[0044] A covering material may be adhered to the filmic material in thearea surrounding the depressions after the removal of solvent from thesolution or suspension filling the depressions. The covering sheet ispreferably an aluminum foil or aluminum foil laminate which may beadhered to the filmic material around the depressions by, for example aheat sensitive material. The cover sheet may be adhered to the filmicmaterial in a manner such that it can be peeled away by the user touncover the oral dosage form in the depression in the mold or,alternatively, it may be adapted for the oral dosage forms to be pushedthrough.

[0045] Alternative methods of forming discrete frozen or gelled units ofthe solution or suspension include solidifying the mixtures in dropwisefashion. For example, the solution or suspension may be passed throughone or more holes to form drops, spheres or a spray of small particleswhich can be solidified by passage through a cold gas or liquid, forexample liquid nitrogen. Alternatively, the drops, spheres or spray maybe solidified by contact with a chilled liquid which is miscible withthe solution or suspension and which has a density such that the dropseither fall through the miscible liquid as they solidify, or float onthe surface of the miscible liquid.

[0046] The suspension or solution prepared in accordance with theprocess of the present invention may also contain other additionalingredients such as coloring agents, flavoring agents, sweetening agentsor preservatives, or fillers such as mannitol or sorbitol which improvethe physical properties of the oral dosage form.

[0047] The product produced by U.S. Pat. No. 5,382,437 to Ecanow isgenerally dimensionally larger than the product of the presentinvention. Based on the data appearing in Example 1 of this reference, aproduct would be produced which has a diameter approximately four tofive times larger than the thickness. Thus, for a thickness of about 4mm, the Ecanow product would have a diameter of about 3 cm. In thepresent invention, the product is dimensionally small r and generallyhas a diameter of about 1 to 1.5 times the thickness of the product. Fora thickness of 4 mm, the diameter may be of the order of about 7 mm.

[0048] The process of the present invention may be used to preparerapidly disintegrating dosage forms of various pharmaceutically activesubstances which have an unacceptable taste. For example, loperamide isincorporated into conventional tablets in the form of its hydrochloridewhich has an unacceptable taste for formulation into a rapidlydisintegrating dosage form. However, the use of loperamide in the formof the-free base enables a palatable dosage form to be produced.Similarly, domperidone is incorporated into conventional tablets in theform of its maleate which has an unacceptable taste for formulation intoa rapidly disintegrating dosage form. However, the use of domperidone inthe form of the free base enables a palatable dosage form to beproduced.

[0049] An advantage of the use of the less soluble forms of thepharmaceutically active substances in the process of the presentinvention is that the less soluble forms are generally easier to freezedry, vacuum dry or dry conventionally.

[0050] The process of the present invention for making more palatablerapidly disintegrating dosage forms obviates the need to use costly drugcoating techniques or complexation techniques to mask the taste of thepharmaceutically active substance. The present invention will be furtherdescribed with reference to the following Examples, which are intendedto be illustrative and not limitative.

EXAMPLE 1

[0051] A solid, oral, rapidly disintegrating dosage form of loperamidewas prepared from loperamide hydrochloride using the followingingredients: QUANTITIES FOR INGREDIENTS 400 UNITS Loperamidehydrochloride 0.800 g Gelatin 2.345 g Mannitol 1.759 g Aspartame 0.300 gMint flavor 0.120 g Sodium hydrogen carbonate 0.150 g Purified water54.526 g

[0052] The gelatin was added to water in a mixing bowl and heated withmixing to approximately 40° C. The mixture was mixed and homogenizedunder vacuum until dissolution of the gelatin was complete.

[0053] The gelatin solution was added to a mixture of mannitol, sodiumhydrogen carbonate and loperamide hydrochloride and the mixture mixedand homogenized until the soluble components had dissolved and thedispersion of the drug particles was complete. The mixture was cooledunder vacuum and aspartame and mint flavor added thereto.

[0054] The suspension was dosed into blister pockets, frozen and freezedried to produce the final dosage form. During the processing theloperamide hydrochloride was converted into the less soluble loperamidefree base form by the sodium hydrogen carbonate buffer.

[0055] The product had an acceptable taste.

EXAMPLE 2

[0056] Domperidone maleate is a poor tasting pharmaceutical compound andwhen initially formulated as a freeze dried rapidly disintegrating oraldosage form, produced an unacceptable product.

[0057] Domperidone was formulated in the form of the free base (which isless soluble in water or saliva than domperidone maleate) into a solid,oral, rapidly disintegrating dosage form using the followingingredients. WEIGHT INGREDIENTS PER UNIT Domperidone (free base) 10 mgAspartame 0.75 mg Peppermint flavor 0.15 mg Gelatin 5.70 mg Mannitol5.20 mg Purified water 128.20 mg

[0058] A solution containing the gelatin and mannitol was prepared andto this was added the aspartame and peppermint flavor. Aliquots of theresulting solution were added to the domperidone powder and a pasteformed on stirring. The remainder of the solution was added andhomogeneous suspension obtained. The suspension was dispensed in 150 mgaliquots into the pockets of a blister pack, frozen and freeze dried toproduce the final dosage form.

[0059] The product had an acceptable taste.

EXAMPLE 3

[0060] The following is an example of conversion of a salt to a freebase. A mixture was formed with the following ingredients: WEIGHTINGREDIENTS PER UNIT Loperamide Hydrochloride 12 g Sodium hydrogencarbonate 2.5 g Gelatin 35 g Mannitol 26 g Water 825.5 g

[0061] The mixture was agitated mixed using a high shear mixer until theloperamide salt was converted to the free base. This was determined bymonitoring the change in crystal morphology using a microscope. Themixture is then dosed into blister pockets, frozen and freeze dried toproduce the final dosage form.

EXAMPLE 4

[0062] The following is an example conversion of a salt to a free acid.A mixture was formed as follows: WEIGHT INGREDIENTS PER UNIT DiclofenacPotassium 50 g Citric Acid 50 g Gelatin 20 g Mannitol 15 g Water 365 g

[0063] The mixture was agitated using a high shear mixer until theconversion was completed. This was determined by monitoring the changein crystal morphology using a microscope. The mixture is then dosed intoblister pockets, frozen, and freeze dried to produce the final dosageform.

EXAMPLE 5

[0064] The following is an example of formation of a hydrate. Hydratesof some drugs have a reduced solubility compared to the anhydrous forms.The formation of a hydrate may be achieved by suspending the drug in anaqueous medium and agitating until the respective hydrate is formed.This process can be accelerated by using heat and a high shear mixing. Asuspension was formed using the following ingredients: WEIGHTINGREDIENTS PER UNIT Thyroxine sodium 1 g Water 500 g

[0065] The suspension was agitated until the thyroxine salt wasconverted to the hydrate form. This was determined by monitoring thechange in crystal morphology using a microscope.

[0066] Industrial Applicability

[0067] While the invention has been described in connection with what ispresently considered to be the most practical and preferred embodiment,it is to be understood that the invention is not to be limited to thedisclosed embodiment, but on the contrary, is intended to cover variousmodifications and equivalent arrangements included within the spirit andscope of the appended claims.

We claim:
 1. A process for the preparation of a solid, oral, rapidlydisintegrating dosage form of a pharmaceutically active substance whichhas an unacceptable taste, which process comprises: a) forming a systemselected from the group consisting of a solution and a suspension in anaqueous or alcoholic solvent of a form of the pharmaceutically activesubstance which is rendered less soluble in the presence of a carriermaterial selected from the group consisting of water-soluble andwater-dispersible carrier materials b) forming discrete units of thesystem; and c) removing the solvent from the discrete units underconditions whereby a network of the carrier material carrying a dosageform the less soluble and more palatable form of the pharmaceuticallyactive substance is formed.
 2. The process according to claim 1 whereinthe pharmaceutically active substance with the unacceptable taste ispresented in a less soluble form prior to formation of said system. 3.The process according to claim 1 wherein the carrier material isgelatin.
 4. The process according to claim 1 wherein the discrete unitsare selected from the group consisting of liquid, frozen and gelledunits.
 5. The process according to claim 4 wherein the discrete unitsare formed in a mold comprising a plurality of pockets.
 6. The processaccording to claim 4 wherein the discrete units are liquid units whichare frozen prior to removal of the solvent.
 7. The process according toclaim 4 wherein the discrete units are frozen units and the solvent isremoved by freeze drying.
 8. The process according to claim 4 whereinsaid units are frozen liquid units and said solvent is removed by vacuumdrying under conditions whereby the solvent is evaporated from saidfrozen units through the liquid phase to a gas.
 9. The process accordingto claim 4 wherein the discrete units are gelled units from which thesolvent is removed by during under conditions selected from the groupconsisting of decreased pressure and forced air drying.
 10. The processaccording to claim 5 wherein the mold comprises at least one depressionin a sheet of a filmic material.
 11. The process according to claim 10wherein a sheet of a covering material is adhered to a filmic materialin the area around at least one said depression after the removal ofsolvent from said system.
 12. The process according to claim 1 whereinthe pharmaceutically active substance is loperamide hydrochloride whichis converted into the form of the loperamide free base during thepreparation of the system.
 13. The process according to claim 1 whereinthe less soluble pharmaceutically active substance is free domperidonebase.
 14. A solid, oral, rapidly disintegrating dosage form of apharmaceutically active substance prepared by a process according toclaim
 1. 15. A solid, oral, rapidly disintegrating dosage form accordingto claim 14 wherein the pharmaceutically active agent is loperamidewhich is present in the composition in the form of the loperamide freebase.
 16. A solid, oral, rapidly disintegrating dosage form comprisingloperamide free base as the pharmaceutically active substance in anetwork of a carrier material selected from the group consisting ofwater-soluble and water-dispersible carrier materials.